1. Field of the Invention
The present invention relates to a therapeutic agent for spinal cord injuries, and more particularly to a therapeutic agent for spinal cord injuries in which hepatocyte growth factor (abbreviated below as “HGF”) protein serves as the active ingredient. The invention also relates to a therapeutic agent for demyelinating diseases in which HGF protein serves as the active ingredient
2. Description of the Related Art
The term “spinal cord injury” (SCI) refers to a clinical state that presents peripheral motor, sensory and autonomous nervous system paralysis below the site of injury to the spinal cord parenchyma from trauma such as dislocation-fracture of the spine as a result of, for example, a traffic accident or a fall from a high place.
The number of spinal cord injury patients is currently about 100,000 in Japan, and some 250,000 in the United States. Each year, the number of such patients increases by at least 5,000 in Japan and at least 10,000 in the U.S.
With recent advances in medical care, the survival rate following injury has risen, and remarkable advances have been made also in methods of reconstructive surgery for spinal cord injuries that are intended to check the progression of disability. As a consequence, success is starting to be achieved in checking secondary neurological deterioration as well. In addition, owing to improvements in rehabilitation technology and the development of supportive devices (electric-powered wheelchairs, etc.), the activities of daily living (ADL) of the patient have improved. However, because of the absence of effective methods for fundamentally treating basic spinal cord injuries (i.e., nerve protection from neurological injury and nerve regeneration), there exist today large numbers of such patients who are unable to relieve themselves, do manual labor or walk without the assistance of others.
HGF was initially identified as a powerful mitogen for mature hepatocytes, and in 1989 was genetically cloned (Biochem. Biophys. Res. Commun. 122, 1450-1459 (1984) and Nature 342, 440-443 (1989)). Although discovered as hepatocyte growth factor, from numerous recent studies in expression and functional analysis that include knockout/knockin mouse techniques, HGF has also been found to be a novel neurotrophic factor (Nat. Neurosci. 2, 213-217 (1999) and Clin. Chim Acta., 327, 1-23 (2003)).
In WO 03/045439, working examples are described in which the effects of the HGF gene on Parkinson's disease model rats were behaviorally and histologically investigated. The experimental results presented therein indicate that the prior administration of HGF gene had the effect of protecting dopamine neurons in the mesencephalic substantia nigra from the neurotoxin 6-hydroxydopamine (6-OHDA). WO 03/045439 also states that, based on these experimental results, the HGF gene can be used in the treatment of not only Parkinson's disease, but other neurological disorders as well, including Alzheimer disease, spinocerebellar degeneration, multiple sclerosis, striatonigral degeneration (SND), spinal muscular atrophy (SMA), Huntington chorea, Shy-Drager syndrome, Charcot-Marie-Tooth disease (CMT), Friedreich ataxia, myasthenia gravis, moyamoya disease, amyloidosis, pick disease, subacute myeloopticoneuropathy, dermatomyositis/polymyositis, Creutzfeldt-Jacov disease, Behcet syndrome, systemic lupus erythematosus (SLE), sarcoidosis, periarteritis nodosa (PN), ossification of posterior longitudinal ligament, diffuse spinal canal stenosis, mixed connective tissue disease (MCTD), diabetic peripheral neuritis and ischemic cerebrovascular disorders (e.g., cerebral infarction, cerebral hemorrhaging), and moreover mentions spinal cord injuries as one such type of neurological disorder.
However, 6-OHDA is a special synthetic toxin which has a specific effect on neurons that synthesize catecholamines (specifically, noradrenaline-, adrenaline- and dopamine-producing neurons), and does not exhibit any toxicity against the neurons which are reportedly degenerated or killed in most of the diseases listed above. Therefore, it is impossible to predict the effects on the above disorders, including spinal cord injuries, from the neuronal cell death-suppressing effects by 6-OHDA. In addition, WO 03/045439 makes no mention of the therapeutic effects of administering HGF protein.
The Journal of the Japanese Orthopaedic Association, Vol. 79, No. 8, pS764 (Aug. 25, 2005) mentions that, when a virus vector containing the HGF gene (an HGF-expressing virus vector) was injected into the spinal cord of rats at the tenth thoracic vertebra and a vertebral crushing injury was then created at the same site, the recovery of lower limb motor function was observed in subsequent evaluations of motor function.
Yet, in spite of the fact that spinal cord injuries generally arise from external trauma suffered in accidents and the like, in The Journal of the Japanese Orthopaedic Association, Vol. 79, No. 8, pS764 (Aug. 25, 2005), the HGF-expressing virus vector was injected 3 days prior to the thoracic vertebral crushing injury. Clearly, it is impossible to predict in this way the occurrence of an accident and the site of injury and to locally administer HGF-expressing virus vector beforehand.
Moreover, the condition of a spinal cord injury patient is likely to be unstable for 72 hours following the trauma, which may make it very difficult to insert a catheter for intrathecal administration. Determining the proper period of administration is thus important.
In addition, there are a number of conceivable problems, such as the difficultly of controlling the amount of protein expressed in conventional HGF gene therapy, the danger with some gene expression vectors of triggering an immune response with repeated administration, and the possibility with some gene expression vectors of introducing genes into the genome.
The nerve fibers of myelinated nerves, including the nerves of the spinal cord, are covered with a sheath composed of a layer of lipoprotein called myelin. This myelin sheath functions as an insulator for the nerve fibers, enabling saltatory conduction by the myelinated nerve. The destruction of this myelin sheath is referred to as demyelination. When demyelination occurs, a variety of neurological symptoms arise due to a dramatic slowing of neurotransmission. Diseases accompanied by such demyelination are generally referred to as demyelinating diseases, and typically include, for example, multiple sclerosis. Spinal cord injuries, too, are generally accompanied by demyelination.
Multiple sclerosis is a slowly progressing central nervous system disease characterized by the formation of disseminated demyelinating plaques. The incidence of multiple sclerosis is about 50 to 100 cases per 100,000 people in Europe and the United States, and is about 1 to 5 cases per 100,000 people in Japan. The symptoms vary widely from individual to individual, and may include loss of vision, double vision, nystagmus, articulation disorders, weakness, abnormal sensations, bladder problems and mood swings. The disease progresses with the repeated remission and resumption of such symptoms. The cause, while not yet determined, is suspected to be an immunological abnormality. Hence, as with other demyelinating diseases, no fundamental treatment currently exists.
As indicated above, although methods involving the injection of an HGF gene-containing virus vector (HGF expression virus vector) are known, it is also known that viruses such as a herpes virus (HSV) or an adenovirus produce a concentration-dependent inflammatory reaction in the brain when such viruses are introduced into the brain, inviting demyelination (WO 05/100577).
Therefore, from this perspective as well, treatment methods involving the use of an HGF gene-containing virus vector clearly do not constitute a fundamental approach toward the treatment of demyelinating disease. A desire thus exists for the establishment of a method of treatment that does not invite demyelination.